1. Field of the Invention
The present invention generally relates to recombinant human progenitor cells, engineered human thymocytes, and engineered human T cells, and methods of treating subjects therewith.
2. Description of the Related Art
There are currently no known therapeutic cures for a variety of chronic viral infections. Many viruses, including human immunodeficiency virus (HIV), hepatitis B virus (HBV), hepatitis C virus (HCV), various herpes family viruses (herpes simplex virus type 1 and 2, Varicella-Zoster virus, Epstein-Bar virus, etc), human papillomavirus, and many others establish a persistent, often lifelong infection with the host organism. Such chronic viral infections are often accompanied with significant morbidity and a lower quality of life. The persistence of these chronic viral infections is due in part to the inability of the human immune system to adequately control and ultimately clear the virus from the body and the lack of effective therapies and medicines that can clear the virus from the body.
In many of these viral infections, the cytotoxic T lymphocyte (CTL) response is important in controlling viral replication and the failure of this response may significantly contribute to the inability of the body to fully control or clear the virus. See Berzofsky, et al. (2004) J Clin Invest. 114(4): 450-462. For example, the CD8+ T cell CTL response plays an important role in controlling the amount of Human Immunodeficiency Virus type 1 (HIV-1) in the body of an infected individual. See Benito, et al. (2004) AIDS Rev. 6(2): 79-88; Borrow, et al. (1994) J Virol. 68(9): 6103-6110; and Rowland-Jones, et al. (2001) Immunol Lett. 79(1-2): 15-20. CTLs specific for various HIV-1 antigenic epitopes are primarily responsible for the initial control and lowering of the viral load in the body shortly after infection with HIV and are responsible for controlling viral loads throughout infection. See Koup, et al. (1994) J Virol. 68(7): 4650-4655. Inevitably, the CTL response in HIV infected individuals fails during the natural course of infection. The loss of the HIV-specific immune response, particularly the CTL response, is associated with an increase in the HIV viral load and a more rapid progression to AIDS and death. See Goulder, et al. (1997) Nat Med. 3(2): 212-217; and Huynen & Neumann (1986) Science. 272(5270): 1962. The virus itself, placed under selective pressure by the CTL response, mutates to avoid the CTL response. See Wolinsky, et al. (1996) Science. 272(5261): 537-542. This results in the virus escaping immune surveillance and is usually followed by the generation of new CTLs to different antigenic epitopes.
One method of augmenting CTL responses is to generate homologous antigen-specific CTLs ex vivo and then administer the ex vivo generated cells into the subject to be treated. This treatment has been effective for treating cytomegalovirus (CMV) and Epstein-Barr virus (EBV) chronic infections, however, this treatment has not been shown to be effective in treating HIV infected individuals. See Lieberman, et al. (1997) Blood. 90(6): 2196-2206; Brodie, et al. (1999) Nat Med. 5(1): 34-41; Bollard, et al. (2004) Biol Blood Marrow Transplant. 10(3): 143-55; and Joseph, et al. (2008) J Virol. 82(6): 3078-3089. In HIV infected individuals, the ex vivo generated CTLs are likely to be dysfunctional as the autologous CTLs are ineffective at clearing or controlling the viral infection as a direct result of the HIV infection and ongoing viral-induced pathology.
Several studies have demonstrated the ability of cloned, antigen specific TCR α-chains and β-chains to be genetically transferred into autologous, stimulated CD8+ T lymphocytes and generate antigen-specific cells. See Hughes, et al. (2005) Hum Gene Ther. 16(4): 457-472; Johnson, et al. (2006) J Immunol. 177(9): 6548-6559; Miles, et al. (2006) Curr Med Chem. 13(23): 2725-2736; and Morgan, et al. (2006) Science. 314(5796): 126-129. Genetic transfer of a cloned human TCR to the melanoma antigen MART-1 into autologous CD8+ T lymphocytes followed by re-infusion of the cells into cancer patients with metastatic melanoma resulted in tumor cell regression in treated individuals. Unfortunately, these autologous cells taken from the treated patient have to undergo extensive ex vivo manipulation to express the transgenic TCR following re-infusion, which could at least partially explain the large amount of MART-1 TCR specific cells that were functionally deficient in this study. In addition, while the cells in this study were maintained for a relatively long period of time, long-term regeneration of antigen-specific cells was limited and the methodology of the study does not allow the generation of antigen-specific cells of a “naïve”, or non-exhausted or unmanipulated, phenotype and thus lack the robust ability to respond and function.
With all the advances in stem cell technology today, the prior art has yet to provide recombinant human progenitor cells, engineered human thymocytes (which may be naïve cells), and engineered human T cells which express a human TCR specific for a target antigen, such as an HIV antigen, that may be used to effectively treat a human subject against a disease or infection involving the expression of the target antigen. Thus, a need still exists for such compositions and methods, especially for treating chronic viral infections where the virus inhibits or impairs the native CTL response.